In type 1 diabetes, autoimmune destruction of insulin-secreting ss-cells in pancreatic islets results in hyperglycemia and its related acute and chronic complications. Recent successes in islet transplantation using the Edmonton protocol have demonstrated that islet transplantation can effectively reverse the metabolic abnormalities associated with diabetes;however, these results have also clearly demonstrated that the liver can be detrimental to long-term islet function, and alternative sites are needed. We propose to investigate the extrahepatic transplantation of human islets, with the objective of designing microporous scaffolds to engraft the islets with the host tissue, which contrasts with the encapsulation approach to isolate the islets from the host tissue to protect against the immune response. The ultimate translation of the engraftment approach would rely on the immunosuppressive regimens that are currently used clinically. Using a mouse model, we have demonstrated that the scaffold provides a support for attachment, maintains a space for cell infiltration, and can present signals that would normally be provided by the extracellular matrix (ECM). Disruption of the islets'ECM during purification has been implicated as a factor that limits islet survival and function in vivo and the scaffold can replace these proteins. We are also proposing that protein delivery from the scaffold has the potential to promote the survival, engraftment, and function of transplanted islets. This proposal seeks to translate the success with murine islets to human islets. Mouse and human islets have a fundamentally different architecture and thus may have differing requirements for the extracellular environment. Thus, the current study will address the hypothesis that microporous scaffolds can be used to create a microenvironment to promote the engraftment, survival and function of transplanted human islets. The Specific Aims for this project are: 1) to establish a foundation for the transplantation of human islets on microporous scaffolds by examining the role of scaffold pore size and thickness on islet engraftment, 2) to investigate the impact of presenting extracellular matrix proteins on the microporous scaffold on the engraftment and function of transplanted human islets, and 3) to test the hypothesis that polymer scaffolds can be used to deliver peptide hormones (exendin-4 and prolactin) to enhance the engraftment and function of human islets. The successful project will identify factors limiting human islet engraftment and whether ECM proteins and trophic factors have the potential to overcome these limitations. PUBLIC HEALTH RELEVANCE: Transplantation of islets or, ultimately, insulin-secreting cells from other sources represents a potential cure for diabetes, which results from destruction of insulin-secreting cells by the immune system. To enhance cell replacement therapy for diabetes, we have developed scaffolds for transplantation of islets or insulin-secreting cells into peritoneal fat that have been successful in a mouse model. In this proposal, we investigate the ability of the scaffolds to enhance engraftment and function of human islets.